Abstract 3389: Analysis of the hepatocellular carcinoma transcriptome reveals dysregulation in pathways implicated in immunotherapy efficacy

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality in the world, but current treatment options are very limited in efficacy for patients who are diagnosed late, which often occurs because of limitations in current screening methods. Immunotherapy has emerged in recent years as arguably the most effective treatment for advanced HCC, but the failure of a large percentage of patients to respond to immunotherapy remains the ultimate obstacle to successful treatment. A phase I clinical trial with CTLA-4 checkpoint blockade has only achieved a 17.6% partial response rate in patients with advanced HCC, while another clinical trial using the PD-1 checkpoint inhibitor nivolumab has reported 18% partial response. Etiology-associated dysregulation of immune-associated (IA) genes may be able to explain the development of this differential clinical response. Using large-scale RNA-sequencing data from The Cancer Genome Atlas (TCGA), we identified immune-associated genes potentially dysregulated by alcohol or viral hepatitis B in HCC. Thirty-four dysregulated IA genes exhibiting significant correlation of gene expression to survival data and clinical variables were identified. To investigate the molecular mechanism for their dysregulation and explore the possibility of genome-based patient stratification, we profiled the correlation of all genomic alterations in HCC patients to IA gene expression using the information theory-based algorithm REVEALER. We also studied gene expression regulators and identified multiple microRNAs implicated in HCC pathogenesis that can potentially regulate these IA genes’ expression. Finally, we validated the dysregulation of several genes by alcohol, including the downregulation of NDRG2 and SOCS2, in vitro using HCC cell lines. Our study identified several potentially key pathways, including the IL-7 pathway, TNFRSF4 (OX40)- NF-κB pathway, and IL-10 pathway, that may be targeted in HCC immunotherapy treatments as well as possible sources of dysregulation for pathways known to be implicated in HCC immunotherapy efficacy. Lastly, we present microRNAs as promising therapeutic targets for dysregulated IA genes because of their extensive regulatory roles in the cancer immune landscape. Citation Format: Wei Tse Li, Christine O. Honda, Yuanhao Qu, Thomas K. Honda, Omar A. Saad, Jessica Wang-Rodriguez, Weg M. Ongkeko. Analysis of the hepatocellular carcinoma transcriptome reveals dysregulation in pathways implicated in immunotherapy efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3389.